DESCRIPTION: (Applicant's Abstract) The long term goal of this project is the chemical synthesis of heterocyclic systems based on certain alkaloid structures which will exhibit desirable therapeutic properties and which may ultimately lead to medicinal agents of value in the treatment of human diseases. The specific purpose of the research is to prepare by rational and efficient synthetic methods alkaloids of the pyrrolizidine, spiroindolizidine, and spiroquinolizidine families so that they can be fully evaluated for bioactivity in screening programs, including the NCI's anti-HIV and anticancer screens. The pyrrolizidine alkaloids targeted for synthesis embrace a family of polyhydroxylated substances known as alexines, and which includes the related substance casuarine. The latter has demonstrated antiviral properties, including anti-HIV activity, and it appears likely that similar biological activity may be exhibited by other members of the group. The synthesis plan for the alexines employs a novel strategy which relies upon ring-closing metathesis coupled to transannular cyclization of a derived azacyclooctane epoxide to assemble the parent pyrrolizidine nucleus. If this strategy proves successful, it will be extended to the synthesis of polyhydroxylated indolizidines, specifically castanospermine. This alkaloid has shown promising antiviral and anticancer activity. A second pyrrolizidine alkaloid targeted for synthesis is based on a spirotricyclic nucleus and is represented by the millipede pheromone nitropolyzonamine. The synthesis plan in this case employs an asymmetric route in which the complete spirocycle is elaborated in a single biomimetic cyclization. This approach will be extended to the related dendrobatid alkaloids from the skin of Panamanian poison-frogs. Synthesis of a marine alkaloid containing the azaspiro(6.5)decane skeleton, halichlorine, is projected in which the spiro system is constructed through asymmetric, transannular nitrone cycloaddition. This and related alkaloids are potential candidates for the treatment of inflammatory diseases and are known inhibitors of the enzyme phospholipase. The final project is a synthetic approach to the spiroquinolizidine alkaloid gymnodimine, a biotoxin which exhibits neurotoxic action in a mouse bioassay. A key step in the approach to this complex structure involves an asymmetric Diels-Alder reaction to assemble the azaspiroundecadiene nucleus of the alkaloid.